In a PET method, a labeled compound labeled with short-lived radionuclide that emits positron is administered into a living body, γ rays generated by this labeled compound (hereinafter, referred to as “tracer”) are measured by using a PET camera (a detector including a gamma-ray scintillator and a photomultiplier), and the distribution thereof in the body is imaged by using a computer. This PET method is used in identification of a site of a tumor such as a cancer cell as an examination of nuclear medicine; a diagnosis of Alzheimer disease, brain infarction, and the like; a diagnosis of a mental disorder such as depression; an evaluation of treatment; and an evaluation of pharmacokinetics and drug efficacy.
A PET method uses a tracer labeled with a short-lived radionuclide such as 11C, 18F, and the like. Among them, a 11C-labeled tracer has many advantages as mentioned below.
(1) Since a 11C-labeled tracer uses a carbon atom existing in all organic compounds, it is applicable in an extremely wide range.
(2) A method for preparing compounds such as 11CH3I, 11CO, 11CO2 serving as a precursor for synthesizing a 11C-labeled tracer is well established. Therefore, purified precursors can be stably obtained.
(3) Since a 11C-containing tracer has a short half-life (20.3 min), it is possible to carry out a large number of trials and clinical tests for basic studies in a day. Furthermore, it is not necessary to pay a particular attention to processing of radiolabeled byproducts generated after a synthesis reaction, and the like.
Therefore, it can be said that the 11C-labeled tracer is the most excellent tracer used in the PET method. However, since the half-life of 11C is such an extremely short time as 20 minutes, it is necessary to carry out purification and administration of the product within 40 minutes after starting the reaction. Therefore, a synthesizing reaction of the tracer has to be completed for about 5 to 10 minutes. A method for carrying out a rapid reaction in a high yield has not been established, which has been an obstacle in using a 11C-labeled tracer in the PET method.
By the way, a method for synthesizing a PET tracer using 11C as a radionuclide includes a method of binding a 11C-labeled methyl group to a heteroatom such as O, C, N, and the like, and a method of binding a 11C-labeled methyl group to carbon of the carbon skeleton. The tracers obtained by binding a 11C-labeled methyl group to a heteroatom such as O, C, N, and the like, are often changed into other compounds rapidly by the metabolism in the body. Therefore, when such tracers are clinically used, the tracers may be changed before they reach the target organ, thus making it impossible to conduct a diagnosis and to provide a treatment accurately. Furthermore, since a compound after methylation shows an utterly different bioactivity from that of a compound before methylation, it is not suitable as a means for searching a candidate for drug discovery. On the contrary, the tracer obtained by binding 11C methyl to carbon of the carbon skeleton has the following advantages: (1) Since a methyl group is a three-dimensionally smallest and non-polar functional group, the effect of the methyl group on the parent compound after it is introduced is minimum; and (2) Since a C-methylated product shows higher stability with respect to the metabolism as compared with an O-methylated product or a N-methylated product, the resultant image has higher reliability and an appropriate diagnosis of disease can be conducted.
Under such circumstances, the present inventors have developed a rapid methylation method in which methyl iodide and an organic tin compound are subjected to a Stille-coupling reaction, and received much attention (non-patent document 1). This method has enabled a cross coupling between SP2 and SP3 carbons atoms, which has been considered to be conventionally difficult in the Stille-coupling reaction. For example, when methyl iodide, an excess tributyl(phenyl)stannane, tri-o-tolylphosphine and unsaturated palladium are reacted in a DMF solvent in the presence of copper salt and potassium carbonate at 60° C. for 5 minutes, methylation proceeds in a yield of 90% or more. This method has been demonstrated to be useful. For example, this method has been actually applied to a prostaglandin derivative tracer and succeeded in imaging a prostaglandin receptor in the human brain.
Besides, the Stille-coupling reaction relating to the present invention has been described in the below mentioned documents (non-patent documents 2 to 4).
[Non-patent document 1] M. Suzuki, H. Doi, M. Bjorkman, Y. Anderson, B. Langstrom, Y. Watanabe and R. Noyori, Chem. Eur. J., 1997, 3(12), 2039-2042
[Non-patent document 2] K. Menzel and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 3718-3719
[Non-patent document 3] H. Tang, K. Menzel and G. C. Fu, Angew, Int. Ed. Engl., 2003, 42, 5079-5082
[Non-patent document 4] J. Baldwin et al, Angew. Chem. Int. Ed., 2004, 43, 1132-1136